EP3325013B1 - Stimulateurs / activateurs de guanylate cyclase soluble en combinaison avec un inhibiteur de l'endopeptidase neutrale (nep) et/ou un antagonist d'angiotensin ii et son utilisation - Google Patents

Stimulateurs / activateurs de guanylate cyclase soluble en combinaison avec un inhibiteur de l'endopeptidase neutrale (nep) et/ou un antagonist d'angiotensin ii et son utilisation Download PDF

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EP3325013B1
EP3325013B1 EP16739146.5A EP16739146A EP3325013B1 EP 3325013 B1 EP3325013 B1 EP 3325013B1 EP 16739146 A EP16739146 A EP 16739146A EP 3325013 B1 EP3325013 B1 EP 3325013B1
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formula
amino
biphenyl
ylmethyl
sgc
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EP3325013A1 (fr
EP3325013B2 (fr
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Tobias Marquardt
Markus Follmann
Johannes-Peter Stasch
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Bayer Pharma AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to stimulators and / or activators of soluble guanylate cyclase in combination with an inhibitor of neutral endopeptidase and / or angiotensin AII antagonists and their use for the treatment and / or prophylaxis of cardiovascular diseases e.g. Heart failure with preserved ejection fraction or heart failure with reduced ejection fraction, renal diseases e.g. chronic kidney failure, urological diseases, lung diseases, diseases of the central nervous system, for the regulation of cerebral blood flow e.g. in vascular cerebral dementia, for the treatment and / or prophylaxis of fibrotic diseases and other symptoms (e.g. end organ damage that affects the brain, kidneys or heart).
  • cardiovascular diseases e.g. Heart failure with preserved ejection fraction or heart failure with reduced ejection fraction
  • renal diseases e.g. chronic kidney failure
  • urological diseases e.g. chronic kidney failure
  • lung diseases e.g. chronic kidney failure
  • urological diseases e.g. chronic kidney failure
  • cyclic guanosine monophosphate cGMP
  • NO nitric oxide
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP).
  • GTP guanosine triphosphate
  • the previously known representatives of this family can be divided into two groups according to structural features and also according to the type of ligands: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by NO.
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is of central importance for the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. In contrast, heme-free preparations cannot be stimulated by NO. Carbon monoxide (CO) is also able to bind to the central iron atom of the heme, whereby the stimulation by CO is significantly less than that by NO.
  • the particulate, membrane-bound guanylate cyclases consist of the cytosolic catalytic domain, a transmembrane region and the extracellular ligand-binding domain.
  • natriuretic peptides The binding of natriuretic peptides to the extracellular ligand-binding domain leads to the activation of the catalytic domain and the biosynthesis of cGMP from GTP.
  • Neutral endopeptidase (neprilysin) inactivates natriuretic peptides through proteolytic cleavage and consequently has an inhibiting effect on the particulate guanylate cyclase.
  • guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signal transmission and in diseases, which are based on a disruption of the above processes.
  • the NO / cGMP system can be suppressed, which can lead, for example, to high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
  • the native as well as the heme-free forms of the soluble guanylate cyclase are activated or stimulated directly by sGC activators and stimulators.
  • sGC activators it is possible to directly stimulate oxidized forms of soluble guanylate cyclase and ultimately also the heme-free form of sGC independently of NO.
  • This oxidized / heme-free form could accumulate in higher concentrations in tissues that are exposed to oxidative stress, so that the use of sGC activators should also lead to a targeted treatment of tissues that are under oxidative stress.
  • LCZ696 is an ARNI (angiotensin receptor neprilysin inhibitor) and thus a dual active ingredient consisting of the angiotensin AII antagonist valsartan and the neprilysin inhibitor sacubitril.
  • the neprilysin inhibition leads to a reduced degradation of natriuretic peptides. These mainly work diuretic and natriuretic due to their vasodilating effect on preglomerular vessels. In addition, they can also inhibit sodium reabsorption in proximal tubular sections.
  • a disadvantage of the administration of LCZ696 for lowering blood pressure is that compensatory effects of the heart rate, such as, for example, reflex tachycardia with an accompanying lowering of blood pressure, can be observed.
  • the object of the present invention is therefore to provide combinations of pharmaceutical active ingredients for the treatment of cardiovascular diseases which lower the mean arterial blood pressure and have as little or no effect as possible on the hemodynamic parameters, such as the heart rate. This is intended to overcome the disadvantages described above, the compensatory effects of the heart rate, which are associated with lowering blood pressure.
  • sGC stimulators and / or sGC activators in combination with neprilysin inhibitors and / or angiotensin AII antagonists were investigated under acute and especially chronic use on the assumption that positive effects on blood pressure and heart rate can be shown under experimental conditions, caused by the resulting plasma and tissue cGMP levels.
  • These experimental conditions consist of healthy animals or animals with high blood pressure (e.g. spontaneously hypertensive rats).
  • the experiments with sGC stimulators and / or activators are carried out "head to head" against the sole combination of neprilysin inhibitors and angiotensin AII antagonists, such as LCZ696.
  • the combination of stimulators and / or activators of soluble guanylate cyclase with a neprilysin inhibitor and / or an angiotensin AII antagonist leads to vascular relaxation and / or controllable lowering of blood pressure.
  • the combination is therefore suitable for the treatment and / or prophylaxis of diseases, preferably cardiovascular diseases, in particular for the treatment and / or prophylaxis of heart failure with preserved ejection fraction or heart failure with reduced ejection fraction, renal diseases, lung diseases, and for treatment and / or fibrotic diseases in humans and animals.
  • diseases preferably cardiovascular diseases, in particular for the treatment and / or prophylaxis of heart failure with preserved ejection fraction or heart failure with reduced ejection fraction, renal diseases, lung diseases, and for treatment and / or fibrotic diseases in humans and animals.
  • Angiotensin AII antagonists of the combinations disclosed herein are by way of example and preferably valsartan, losartan, candesartan, telmisartan, irbesartan, olmesartan, eprosartan or azilsartan, and preferably valsartan.
  • Valsartan is the angiotensin AII antagonist (S) -N- (1-carboxy-2-methylprop-1-yl) -N-pentanoyl-N- [2 '- (1H-tetrazol-5-yl) biphenyl-4- yl-methyl] amine of formula (30) or a salt, solvate or solvate of the salts thereof and is in EP 0 443 983 A and U.S. 5,399,578 A described.
  • the NEP inhibitor of the present combinations according to the invention is N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid of the formula (31) or an ester of the acid or in each case a salt, solvate or solvate of the salts of the acid or of the ester.
  • Acid and ester of the NEP inhibitor of the present inventive combinations are in EP 0 555 175 A1 described.
  • N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid is in the form of the ethyl ester, N- (3-carboxy-1-oxopropyl ) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester.
  • preferred salts include the sodium salt, the triethanolamine salt and the tris (hydroxymethyl) aminomethane salt.
  • valsartan and the NEP inhibitor can each be used individually or as trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate ( S ) - 3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate.
  • sGC stimulators and activators within the scope of the present disclosed combinations are the compounds disclosed in the following laid-open specifications: WO03 / 097063 , WO03 / 09545 , WO04 / 009589 , WO03 / 004503 , WO02 / 070462 , WO2007 / 045366 , WO2007 / 045369 , WO2007 / 045370 , WO2007 / 045433 , WO2007 / 045367 , WO2007 / 124854 , WO2007 / 128454 , WO2008 / 031513 , WO2008 / 061657 , WO2008 / 119457 , WO2008 / 119458 , WO2009 / 127338 , WO2010 / 079120 , WO2010 / 102717 , WO2011 / 051165 , WO2011 / 147809 , WO2011 / 141409 , WO2014
  • Preferred sGC stimulators within the scope of the disclosed combinations are the compounds of the formulas (1), (2), (3), (4), (6), (7), (27) and (28).
  • sGC stimulators of the formulas (3), (4), (6), (7) and (28).
  • the sGC stimulators of the formulas (3) and (6) are particularly preferred in the context of the combinations according to the invention.
  • the sGC stimulator of the formula (6) is particularly preferred in the context of the combinations according to the invention.
  • the combinations according to the invention allow an effective treatment of cardiovascular diseases by lowering the mean arterial blood pressure and as little or no effect as possible on the hemodynamic parameters, such as the heart rate.
  • the combinations according to the invention are suitable for the prophylaxis and / or treatment of diseases and lead to a reduction in blood pressure and an increase in coronary blood flow. These effects are mediated via a stimulation of the soluble and / or particulate guanylate cyclase and / or a blockade of the angiotensin receptor.
  • the combinations according to the invention increase the effect of substances that increase the cGMP level, such as, for example, EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • Another object of the present invention is the use of sGC activators and / or sGC stimulators in combination with neprilysin inhibitors and / or angiotensin AII antagonists for the treatment of cardiovascular diseases e.g. Heart failure with preserved ejection fraction or heart failure with reduced ejection fraction, renal diseases e.g. chronic kidney failure, urological diseases, lung diseases, diseases of the central nervous system, for the regulation of cerebral blood flow e.g. in vascular cerebral dementia, for the treatment and / or prophylaxis of fibrotic diseases and other symptoms (e.g. end organ damage that affects the brain, kidneys or heart).
  • cardiovascular diseases e.g. Heart failure with preserved ejection fraction or heart failure with reduced ejection fraction
  • renal diseases e.g. chronic kidney failure
  • urological diseases e.g. chronic kidney failure
  • lung diseases e.g. chronic kidney failure
  • urological diseases e.g. chronic kidney failure
  • lung diseases e.g. chronic kidney failure
  • Another object of the present invention are sGC activators and / or sGC stimulators in combination with angiotensin AII antagonists and their use for the treatment of cardiovascular diseases e.g. Heart failure with preserved ejection fraction or heart failure with reduced ejection fraction, renal diseases e.g. chronic kidney failure, urological diseases, lung diseases, diseases of the central nervous system, for the regulation of cerebral blood flow e.g. in vascular cerebral dementia, for the treatment and / or prophylaxis of fibrotic diseases and other symptoms (e.g. end organ damage that affects the brain, kidneys or heart).
  • cardiovascular diseases e.g. Heart failure with preserved ejection fraction or heart failure with reduced ejection fraction
  • renal diseases e.g. chronic kidney failure
  • urological diseases e.g. chronic kidney failure
  • lung diseases e.g. chronic kidney failure
  • urological diseases e.g. chronic kidney failure
  • lung diseases e.g. chronic kidney failure
  • urological diseases e.g. chronic kidney failure
  • the invention preferably relates to sGC stimulators and / or activators in combination with a neprilysin inhibitor, such as, for example and preferably, sacubitril and / or an angiotensin AII antagonist, such as, for example and preferably, valsartan, losartan, candesartan, telmisartan, irbesartan, olmesartan, eprosartan or Azilsartan.
  • a neprilysin inhibitor such as, for example and preferably, sacubitril and / or an angiotensin AII antagonist, such as, for example and preferably, valsartan, losartan, candesartan, telmisartan, irbesartan, olmesartan, eprosartan or Azilsartan.
  • the present invention preferably relates to combinations containing an sGC stimulator and / or sGC activator, or N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid Esters thereof and / or valsartan and the salts, solvates and solvates of the salts of a sGC stimulator and / or sGC activator, N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4 -amino-2R-methylbutanoic acid or an ester thereof and / or valsartan.
  • Another preferred subject of the present invention are combinations containing an sGC stimulator and / or sGC activator and LCZ696 and in each case the salts, solvates and solvates of the salts thereof.
  • a particularly preferred subject of the present invention are combinations containing an sGC stimulator, sacubitril and / or an angiotensin AII antagonist and the salts, solvates and solvates of the salts thereof.
  • Another particularly preferred subject of the present invention are combinations containing an sGC stimulator, sacubitril and / or valsartan and the salts, solvates and solvates of the salts thereof.
  • Another particularly preferred subject of the present invention are combinations containing an sGC stimulator and LCZ696 and the salts, solvates and solvates of the salts thereof.
  • Another particularly preferred subject of the present invention are combinations containing the compound of the formula (6), N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid or an ester thereof and / or valsartan, and in each case the salts, solvates and solvates of the salts of the compound of the formula (6) and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl ) -4-amino-2R-methylbutanoic acid or an ester thereof and / or valsartan.
  • Another particularly preferred subject of the present invention are combinations containing the compound of the formula (6) and LCZ696 and in each case the salts, solvates and solvates of the salts thereof.
  • the present invention also relates to combinations containing an sGC stimulator and / or sGC activator and valsartan, as well as the salts, solvates and solvates of the salts of an sGC stimulator and / or sGC activator and valsartan.
  • the present invention also relates to combinations containing the compound of the formula (6) and valsartan, and also the salts, solvates and solvates of the salts of the compound of the formula (6) and valsartan.
  • the components to be combined can be present as salts.
  • Physiologically acceptable salts of the compounds to be combined are preferred as salts in the context of the present invention.
  • Another object of the present invention are combinations in which the molar ratio of the compound of formula (6) to valsartan to N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino- 2R-methylbutanoic acid or an ester thereof is 0.01-1: 1: 1.
  • Another object of the present invention are combinations in which the molar ratio of the compound of formula (6) to trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3-ethoxycar-bonyl- 1-butylcarbamoyl) propionate ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate is 0.01-1: 1 .
  • Another object of the present invention are combinations in which the molar ratio of the compound of formula (6) to N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino- 2R-methylbutanoic acid or an ester thereof is 0.01-1: 1.
  • the present invention further provides combinations in which the molar ratio of the compound of the formula (6) to valsartan is 0.01-1: 1.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, where the compound of formula (6) once a day and valsartan and N- (3-carboxy-1-oxopropyl) - (4S) - (p- phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester or N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or an ester thereof can be administered twice daily .
  • the present invention also relates to combinations according to the invention for the treatment and / or prophylaxis of diseases, 1.25-20 mg of the compound of the formula (6), 20-200 mg of valsartan and 20-200 mg of N- (3-carboxy-1- oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or an ester thereof.
  • the present invention also relates to combinations according to the invention for the treatment and / or prophylaxis of diseases, 1.25-20 mg of the compound of the formula (6) and 20-200 mg of N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or an ester thereof.
  • the present invention also relates to combinations according to the invention for the treatment and / or prophylaxis of diseases, 1.25-20 mg of the compound of the formula (6) and 20-200 mg of valsartan being administered
  • the present invention also relates to combinations according to the invention for the treatment and / or prophylaxis of diseases, the compound of the formula (6) being administered once a day and trisodium- [3 - ((1 S , 3 R ) -1-biphenyl-4 -ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate - ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate ] hemipentahydrate is given twice a day.
  • the present invention also relates to combinations according to the invention for the treatment and / or prophylaxis of diseases, 1.25-20 mg of the compound of the formula (6) and 40-400 mg of trisodium [3 - ((1 S , 3 R ) -1 -biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate - ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate.
  • Another object of the present invention are combinations according to the invention, in which the molar ratio of the compound of the formula (6) to valsartan to N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino- 2R-methylbutanoic acid or an ester thereof 0.001-1: 1: 3, 0.001-1: 3: 1, 0.001-1: 1: 2, 0.001-1: 2: 1 or 0.001-1: 1: 1, preferably 0.005- 0.75: 1: 3, 0.005-0.75: 3: 1, 0.005-0.75: 1: 2, 0.005-0.75: 2: 1 or 0.005-0.75: 1: 1 and most preferably 0.01-0.5: 1: 1.
  • Another object of the present invention are combinations according to the invention in which the molar ratio of the compound of the formula (6) to trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl -1-butylcarbamoyl) propionate ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate 0.001-1: 1 , preferably 0.005-0.75: 1 and most preferably 0.01-0.5: 1.
  • the present invention also relates to combinations containing the compound of the formula (29), N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid or the Esters thereof and / or valsartan and in each case the salts, solvates and solvates of the salts of the compound of the formula (29), N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4 -amino-2R-methylbutanoic acid or the ester and / or valsartan thereof.
  • the present invention also relates to combinations containing the compound of the formula (29) and trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate - ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate and the salts, solvates, and solvates of the salts thereof, respectively.
  • the present invention further relates to combinations containing the compound of the formula (29) and valsartan, and also the salts, solvates and solvates of the salts of the compound of the formula (29) and valsartan thereof.
  • Another object of the present invention are combinations in which the molar ratio of the compound of formula (29) to valsartan to N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino- 2R-methylbutanoic acid or the esters thereof is 0.02-1: 1: 1.
  • Another object of the present invention are combinations in which the molar ratio of the compound of formula (29) to trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3-ethoxycar bonyl- 1-butylcarbamoyl) propionate ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate is 0.02-1: 1 .
  • Another object of the present invention are combinations in which the molar ratio of the compound of formula (29) to N- (3-Caiboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino- 2R-methylbutanoic acid or the esters thereof is 0.02-1: 1.
  • the present invention further provides combinations in which the molar ratio of the compound of the formula (29) to valsartan is 0.02-1: 1.
  • the present invention also provides the combinations according to the invention for the treatment and / or prophylaxis of diseases, where the compound of formula (29) once a day and valsartan and N- (3-carboxy-1-oxopropyl) - (4S) - (p -phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester or N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid can be administered twice daily.
  • the present invention further relates to the combinations according to the invention for the treatment and / or prophylaxis of diseases, where 2.5-20 mg of the compound of the formula (29), 20-200 mg of valsartan and 20-200 mg of N- (3-carboxy-1 -oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or the esters thereof.
  • the present invention also relates to the combinations according to the invention for the treatment and / or prophylaxis of diseases, where 2.5-20 mg of the compound of the formula (29) and 20-400 mg of N- (3-carboxy-1-oxopropyl) - (4S ) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or the esters thereof.
  • the present invention also relates to the combinations according to the invention for the treatment and / or prophylaxis of diseases, 2.5-20 mg of the compound of the formula (29), 20-400 mg of valsartan or the esters thereof being administered.
  • the present invention also relates to the combinations according to the invention for the treatment and / or prophylaxis of diseases, the compound of the formula (29) being administered once a day and trisodium [3 - ((1 S , 3 R ) -1-biphenyl- 4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate- ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate is given twice a day.
  • the present invention also relates to the combinations according to the invention for the treatment and / or prophylaxis of diseases, where 2.5-20 mg of the compound of the formula (29) and 40-400 mg trisodium [3 - ((1 S , 3 R ) - 1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate- ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'- ylmethyl ⁇ amino) butyrate] hemipentahydrate.
  • the present invention also provides the combinations according to the invention in which the molar ratio of the compound of the formula (29) to valsartan to N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino -2R-methylbutanoic acid or an ester thereof in the range 0.001-1: 1: 3, 0.001-1: 3: 1, 0.001-1: 1: 2, 0.001-1: 2: 1 or 0.001-1: 1: 1, preferably 0.005-0.75: 1: 3, 0.005-0.75: 3: 1, 0.005-0.75: 1: 2, 0.005-0.75: 2: 1 or 0.005-0.75: 1: 1 and most preferably 0.02-0.5: 1: 1 is.
  • Another object of the present invention are the combinations according to the invention in which the molar ratio of the compound of formula (29) to trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3-ethoxycar- bonyl-1-butylcarbamoyl) propionate ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate 0.001-1: 1, preferably 0.005-0.75: 1 and most preferably 0.01-0.5: 1.
  • the present invention also relates to the combinations according to the invention for the treatment and / or prophylaxis of diseases.
  • Another object of the present invention are the combinations according to the invention for use in a method for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, and for the treatment and / or prophylaxis of fibrotic diseases.
  • the present invention also relates to a medicament containing at least one combination according to the invention in combination with an inert, non-toxic, pharmaceutically suitable auxiliary substance.
  • Another object of the present invention is a medicament containing at least one combination according to the invention in combination with one or more other active ingredients selected from the group consisting of ACE inhibitors, renin inhibitors, beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, Digitalis (digoxin) derivatives, calcium sensitizers, nitrates and antithrombotics.
  • active ingredients selected from the group consisting of ACE inhibitors, renin inhibitors, beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, Digitalis (digoxin) derivatives, calcium sensitizers, nitrates and antithrombotics.
  • Another object of the present invention is a medicament containing at least one combination according to the invention for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, and for the treatment and / or prophylaxis of fibrotic diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, and for the treatment and / or prophylaxis of fibrotic diseases in humans and animals using at least one combination according to the invention.
  • kits that comprises two or three separate units: a pharmaceutical composition of an sGC stimulator and / or sGC activator, a pharmaceutical NEP inhibitor composition and / or a pharmaceutical composition of valsartan.
  • the invention also relates to a preferred kit form which comprises two units: a pharmaceutical composition containing an sGC stimulator and / or sGC activator and a pharmaceutical composition containing an NEP inhibitor and / or valsartan.
  • the invention also relates to a preferred kit form which comprises two units: a pharmaceutical composition containing an sGC stimulator and / or sGC activator and a pharmaceutical composition containing LCZ696.
  • the invention also relates to a preferred kit form which comprises two units: a pharmaceutical composition comprising the compound of the formula (6) and a pharmaceutical composition comprising LCZ696.
  • the invention also relates to a preferred kit form which comprises two units: A pharmaceutical composition comprising the compound of the formula (29) and a pharmaceutical composition comprising LCZ696.
  • the kit is particularly advantageous when the separate components have to be administered in different dosage forms or are administered at different dose intervals.
  • Another object of the present invention is a kit comprising a pharmaceutical composition containing an sGC stimulator and / or sGC activator and a pharmaceutical composition containing an angiotensin AII antagonist and N- (3-carboxy-1-oxopropyl) - (4S) - (p -phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid or the esters thereof.
  • Another object of the present invention is a kit comprising a pharmaceutical composition containing an sGC stimulator and / or sGC activator and a pharmaceutical composition containing valsartan and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl- methyl) -4-amino-2R-methylbutanoic acid or the esters thereof.
  • Another object of the present invention is a kit comprising a pharmaceutical composition containing an sGC stimulator and / or sGC activator and a pharmaceutical composition containing trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3- ethoxycarbonyl-1-butylcaibamoyl) propionate ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate.
  • Another object of the present invention is a kit comprising a pharmaceutical composition containing the compound of formula (6) and a pharmaceutical composition containing valsartan and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl ) -4-amino-2R-methylbutanoic acid or the esters thereof.
  • kits comprising a pharmaceutical composition containing the compound of formula (6) and a pharmaceutical composition containing trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3- ethoxycarbonyl-1-butylcarbamoyl) propionate ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate.
  • Another object of the present invention is a kit comprising a pharmaceutical composition containing the compound of formula (29) and a pharmaceutical composition containing valsartan and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl ) -4-amino-2R-methylbutanoic acid or the esters thereof.
  • kits comprising a pharmaceutical composition containing the compound of formula (29) and a pharmaceutical composition containing trisodium [3 - ((1 S , 3 R ) -1-biphenyl-4-ylmethyl-3- ethoxycarbonyl-1-butylcarbamoyl) propionate ( S ) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate.
  • the combinations according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as high blood pressure (hypertension), resistant hypertension, acute and chronic heart failure, heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF), coronary heart disease and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, arrhythmias of the atria and ventricles as well as conduction disorders such as atrio-ventricular blockades I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial fibrillation, ventricular fibrillation, ventricular tachyarrhythmia, torsade de pointes tachycardia, extrasystoles of the atrium and ventricle, AVjunctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentry tachycardia, Wolff-Parkinson
  • heart failure includes both acute and chronic forms of heart failure, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital cardiopathic, idiomyopathy heart failure heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic regurgitation, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve, combined heart valve defects, heart muscle inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcohol-toxic cardiomyopathy, cardiac storage diseases, diastolic cardiac insufficiency and systolic heart failure and acute phases of worsening of existing chronic heart failure (worsening heart failure
  • the combinations according to the invention can also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinaemia, dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia, hypercholesterolaemia, abetelipoproteinemia, sitosterolaemia, xanthomatosis, combined obesity and obesity (obesity) (obesity) (Tangier disease, obesity) as well as the metabolic syndrome.
  • the combinations according to the invention can be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, of microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrene, CREST syndrome, erythematosis, onychomycosis , rheumatic diseases as well as to promote wound healing.
  • the combinations according to the invention are also suitable for the treatment of muscular dystrophy, such as the Becker-Kiener muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD).
  • the combinations according to the invention are also suitable for the treatment and / or prophylaxis of urological diseases such as, for example, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feline urological syndrome (FUS), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI , OUI), pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostate syndrome
  • BPH benign prostate hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • FUS lower urinary tract syndromes
  • UI incontinence
  • MUI UUI, SUI , OUI
  • pelvic pain benign and mal
  • kidney insufficiency encompasses both acute and chronic manifestations of renal insufficiency, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, and tubulosclerosis diseases and congenital kidney disease, kidney inflammation, immunological kidney disease such as kidney transplant rejection, immune complex-induced kidney disease, toxic substance-induced nephropathy, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, which are diagnosed by nephrotic syndrome, nephrosclerosis, hypertensive syndrome, for example, abnormal
  • the present invention also includes the use of the combinations according to the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (e.g. hyperkalaemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (e.g. hyperkalaemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • the combinations according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, lung diseases such as e.g. pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including pulmonary hypertension associated with left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoid, COPD or pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute (ARDS), acute lung damage (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (e.g. pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
  • lung diseases such as e.g. pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including pulmonary hypertension associated with left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH),
  • the combinations described in the present invention also represent combinations for the treatment and / or prophylaxis of diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
  • they are suitable for improving perception, concentration, learning or memory after cognitive disorders, such as those that occur in particular in situations / diseases / syndromes such as "mild cognitive impairment", age-associated learning and memory disorders, age-associated memory losses, vascular dementia, skull-brain -Trauma, stroke, dementia that occurs after strokes ("post stroke dementia”), post-traumatic head and brain trauma, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies , Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV
  • the combinations according to the invention are also suitable for regulating the cerebral blood flow and are, for example, effective agents for combating vascular cerebral dementia and migraines. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (apoplexia cerebri) such as stroke, cerebral ischemia and the Traumatic brain injury.
  • the combinations according to the invention can also be used to combat painful conditions and tinnitus.
  • the combinations according to the invention have an anti-inflammatory effect and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory eye diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammation
  • Crohn's Disease UC
  • pancreatitis inflammatory diseases of the kidney
  • Peritonitis rheumatoid diseases
  • inflammatory skin diseases and inflammatory eye diseases.
  • combinations according to the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
  • the combinations according to the invention can be used for the treatment and / or prophylaxis of fibrotic diseases of the internal organs, such as, for example, the lungs, heart, kidneys, skin, bone marrow and especially the liver, as well as dermatological fibroses and fibrotic diseases of the eye.
  • fibrotic diseases of the internal organs such as, for example, the lungs, heart, kidneys, skin, bone marrow and especially the liver, as well as dermatological fibroses and fibrotic diseases of the eye.
  • fibrotic diseases includes in particular the following terms liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic diseases, systemic sclerosis, scleroderma, Morphea, keloids, hypertrophic scarring (even after surgical interventions), naevi, diabetic retinopathy, proliferative vitroretinopathy and diseases of the connective tissue (e.g. sarcoid).
  • connective tissue e.g. sarcoid
  • the combinations according to the invention are also suitable for combating postoperative scarring, e.g. as a result of glaucoma operations.
  • the combinations according to the invention can also be used cosmetically on aging and keratinizing skin.
  • the combinations according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, bone formation disorders, glaucoma and gastroparesis.
  • Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the combinations according to the invention are administered in combination with a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the combinations according to the invention are administered in combination with a thrombin inhibitor such as, for example and preferably, ximelagatran, dabigatran, melagatran, bivalirudin or clexane.
  • a thrombin inhibitor such as, for example and preferably, ximelagatran, dabigatran, melagatran, bivalirudin or clexane.
  • the combinations according to the invention are administered in combination with a GPIIb / IIIa antagonist such as, for example and preferably, tirofiban or abciximab.
  • the combinations according to the invention are used in combination with a factor Xa inhibitor, such as, for example and preferably, rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as, for example and preferably, rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC
  • the combinations according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the combinations according to the invention are administered in combination with a vitamin K antagonist such as, for example and preferably, coumarin.
  • Compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists are preferred among the antihypertensive agents as well as diuretics.
  • the combinations according to the invention are administered in combination with a calcium antagonist such as, for example and preferably, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, for example and preferably, nifedipine, amlodipine, verapamil or diltiazem.
  • the combinations according to the invention are administered in combination with an alpha-1 receptor blocker such as, for example and preferably, prazosin.
  • the combinations according to the invention are used in combination with a beta-receptor blocker, such as, for example and preferably, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindolol.
  • a beta-receptor blocker such as, for example and preferably, propranolol, atenolol, timolol, pindolo
  • the combinations according to the invention are administered in combination with an angiotensin AII antagonist such as, for example and preferably, losartan, candesartan, valsartan, telmisartan or embursatan.
  • angiotensin AII antagonist such as, for example and preferably, losartan, candesartan, valsartan, telmisartan or embursatan.
  • the combinations according to the invention are administered in combination with an ACE inhibitor such as, for example and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, for example and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the combinations according to the invention are administered in combination with an endothelin antagonist such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the combinations according to the invention are administered in combination with a renin inhibitor such as, for example and preferably, aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as, for example and preferably, aliskiren, SPP-600 or SPP-800.
  • the combinations according to the invention are administered in combination with a mineralocorticoid receptor antagonist such as, for example and preferably, spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as, for example and preferably, spironolactone or eplerenone.
  • the combinations according to the invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics such as amiloride and triamterene, with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenonics such as thiazide diuretics, for example Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
  • a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium-sparing diuretics such as amiloride and triamterene
  • aldosterone antagonists such as spironolactone
  • potassium canrenoate and eplerenonics such as thiazide diuretics, for example Hydrochlorothiazide, chlorthalidone, xipamide, and ind
  • Agents which change lipid metabolism are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR -gamma- and / or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.
  • cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors PPAR-alpha, PPAR -gamma- and / or PPAR-delta agonists
  • cholesterol absorption inhibitors polymeric bile acid adsorbers
  • the combinations according to the invention are administered in combination with a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the combinations according to the invention are administered in combination with a thyroid receptor agonist such as, for example and preferably, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or Axitirome (CGS 26214).
  • a thyroid receptor agonist such as, for example and preferably, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or Axitirome (CGS 26214).
  • the combinations according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the combinations according to the invention are administered in combination with a squalene synthesis inhibitor such as, for example and preferably, BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as, for example and preferably, BMS-188494 or TAK-475.
  • the combinations according to the invention are administered in combination with an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the combinations according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the combinations according to the invention are administered in combination with a PPAR-gamma agonist such as, for example and preferably, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, for example and preferably, pioglitazone or rosiglitazone.
  • the combinations according to the invention are administered in combination with a PPAR-delta agonist such as, for example and preferably, GW 501516 or BAY 68-5042.
  • a PPAR-delta agonist such as, for example and preferably, GW 501516 or BAY 68-5042.
  • the combinations according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • the combinations according to the invention are administered in combination with a lipase inhibitor such as, for example and preferably, orlistat.
  • the combinations according to the invention are administered in combination with a polymeric bile acid adsorber such as, for example and preferably, cholestyramine, colestipol, colesolvam, CholestaGel or colestimid.
  • a polymeric bile acid adsorber such as, for example and preferably, cholestyramine, colestipol, colesolvam, CholestaGel or colestimid.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • the combinations according to the invention are administered in combination with a lipoprotein (a) antagonist such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • the components can act systemically and / or locally.
  • they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the combinations according to the invention can be administered in administration forms suitable for these administration routes.
  • the combinations according to the invention which function quickly and / or in modified form and which contain the compounds which are part of the combination in crystalline and / or amorphized and / or dissolved form are suitable, e.g. Tablets (non-coated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings that control the release of the compounds on which the combinations according to the invention are based), tablets or films / wafers, films / lyophilisates, capsules that disintegrate quickly in the oral cavity (for example hard or soft gelatine capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Tablets non-coated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings that control the release of the compounds on which the combinations according to the invention are based
  • tablets or films / wafers, films / lyophilisates capsules that disintegrate quickly in the oral cavity (for example hard or soft gelatine
  • Preferred forms of administration are tablet form (non-coated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings that control the release of the compounds on which the combinations according to the invention are based), tablets or films / wafers that disintegrate quickly in the oral cavity and Particularly preferred application forms are tablet form (non-coated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings that control the release of the components on which the combinations according to the invention are based), tablets or films / wafers that disintegrate quickly in the oral cavity.
  • Parenteral administration can be done by avoiding an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar
  • absorption e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Application forms suitable for parenteral administration include Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions ( Lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powder, implants or stents.
  • Oral or parenteral administration is preferred, with oral administration being more preferred.
  • Oral administration in tablet form is particularly preferred.
  • the components can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries.
  • auxiliary materials include Carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants) such as ascorbic acid), dyes (for example inorganic pigments such as iron oxides) and taste and / or odor correctors.
  • Carriers e.g. microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • the components can be administered together or sequentially or separately in a combined unit dosage form, in two separate unit dosage forms, or in three separate unit dosage forms.
  • the unit dosage form can also be a fixed combination.
  • a therapeutically effective amount of each component of the combination of the invention can be administered simultaneously or sequentially in any order.
  • the components can be present in what is known as a sustained-release formulation in which the components according to the invention are released at different times.
  • a sustained-release formulation in which the components according to the invention are released at different times.
  • One example is a tablet with delayed dissolving coatings, each containing one or more components of the combinations according to the invention.
  • the dosage of the sGC stimulator and / or sGC activator for oral administration is about 1.25-20 mg, 1.25-5 mg or about 5-10 mg or 10 to 20 mg or.
  • the dosage of valsartan is about 20-110 mg bid, 20-50 mg bid, or 50-110 mg bid.
  • the dosage of the NEP inhibitor is about 20-100 mg bid, about 20-50 mg bid, or 50 to 100 mg bid.
  • the dosage of LCZ696 is about 40-400 mg, 50-200 mg bid, 50-100 mg bid or 100-200 mg bid.
  • valsartan is provided in the form of a suitable unit dosage form, for example a capsule or tablet, and comprises a therapeutically effective amount of, for example, 20 to 320 mg of valsartan that can be administered to patients.
  • the administration of the active ingredient can take place three times a day, starting, for example, from a daily dose of 20 mg or 40 mg of valsartan, which increases to over 80 mg daily and further to 160 mg daily to 320 mg daily.
  • valsartan is administered once a day or twice a day in patients with cardiac insufficiency at a dose of 80 mg or 160 mg each.
  • Corresponding doses can be taken in the morning, at noon or in the evening, for example.
  • Preferred is a q.d. or b.i.d. Administration for heart failure.
  • the NEP inhibitor is administered in unit forms, for example tablets or capsules, for example 20 mg to 800 mg, preferably 50 mg to 700 mg, more preferably 100 mg to 600 mg and even more preferably 100 mg to 300 mg, the once administered during the day.
  • the dosages described above can be formulated within the scope of the invention as a fixed-dose combination, in which the preferred unit forms can be tablets or capsules.
  • the dosage of the sGC stimulator and / or sGC activator is about 2.5-20 mg od
  • the dosage of valsartan is about 25 mg bid and the dosage of the NEP inhibitor is about 25 mg bid
  • the dosage is also preferred of the sGC stimulator and / or sGC activator about 2.5-20 mg od
  • the dosage of valsartan about 50 mg bid and the dosage of the NEP inhibitor is about 50 mg bid and also preferably the dosage of the sGC stimulator and / or sGC activator about 2.5-20 mg od
  • the dosage of valsartan about 100 mg bid and the dosage of the NEP inhibitor is about 100 mg bid.
  • the dosage of the sGC stimulator and / or sGC activator is about 5-10 mg od
  • the dosage of valsartan is about 25 mg bid and the dosage of the NEP inhibitor is about 25 mg bid
  • the dosage is also preferred of the sGC stimulator and / or sGC activator about 5-10 mg od
  • the dosage of valsartan about 50 mg bid and the dosage of the NEP inhibitor is about 50 mg bid and the dosage of the sGC stimulator and / or sGC activator is also preferred about 5-10 mg od
  • the dosage of valsartan about 100 mg bid and the dosage of the NEP inhibitor is about 100 mg bid.
  • the dosage of the sGC stimulator and / or sGC activator is about 2.5-5 mg od
  • the dosage of valsartan is about 25 mg bid and the dosage of the NEP inhibitor is about 25 mg bid
  • the dosage is also preferred of the sGC stimulator and / or sGC activator about 2.5-5 mg od
  • the dosage of valsartan about 50 mg bid and the dosage of the NEP inhibitor is about 50 mg bid and likewise preferably the dosage of the sGC stimulator and / or sGC activator is about 2.5-5 mg od
  • the dosage of valsartan is about 100 mg bid and the dosage of the NEP inhibitor is about 100 mg bid.
  • the dosage of the sGC stimulator and / or sGC activator is about 10-20 mg od
  • the dosage of valsartan is about 25 mg bid and the dosage of the NEP inhibitor is about 25 mg bid
  • the dosage is also preferred of the sGC stimulator and / or sGC activator about 10-20 mg od
  • the dosage of valsartan about 50 mg bid and the dosage of the NEP inhibitor is about 50 mg bid
  • the dosage of the sGC stimulator and / or sGC activator is also preferred about 10-20 mg od
  • the dosage of valsartan about 100 mg bid and the dosage of the NEP inhibitor is about 100 mg bid.
  • the dosage of the sGC stimulator and / or sGC activator is about 2.5-20 mg od and the dosage of LCZ696 is about 50 mg bid, also preferably the dosage of the sGC stimulator and / or sGC activator is about 5 -10 mg od and that of LCZ696 about 100 mg bid and likewise preferably the dosage of the sGC stimulator or sGC activator is about 2.5-5 mg od and the dosage of LCZ696 is about 200 mg bid.
  • the dosage of the sGC stimulator and / or sGC activator is about 10-20 mg od and the dosage of LCZ696 is about 50 mg bid; the dosage of the sGC stimulator and / or sGC activator is also preferably about 10 -20 mg od and that of LCZ696 about 100 mg bid and likewise preferably the dosage of the sGC stimulator and / or sGC activator is about 10-20 mg od and the dosage of LCZ696 is about 200 mg bid.
  • the dosage of the sGC stimulator and / or sGC activator is about 2.5-5 mg od and the dosage of LCZ696 is about 50 mg bid, also preferably the dosage of the sGC stimulator and / or sGC activator is about 2.5 -5 mg od and that of LCZ696 about 100 mg bid and likewise preferably the dosage of the sGC stimulator and / or sGC activator is about 2.5-5 mg od and the dosage of LCZ696 is about 200 mg bid.
  • the dosage of the sGC stimulator and / or sGC activator is about 5-10 mg od and the dosage of LCZ696 is about 50 mg bid, also preferably the dosage of the sGC stimulator and / or sGC activator is about 5 -10 mg od and that of LCZ696 about 100 mg bid and also preferably the dosage of the sGC stimulator and / or sGC activator is about 5-10 mg od and the dosage of LCZ696 is about 200 mg bid.
  • a commercially available telemetry system from Data Sciences International DSI, USA, was used.
  • the system consists of 3 main components: (1) implantable transmitters (PhysioTel® telemetry transmitter), (2) receivers (PhysioTel® receivers) which are connected to a (3) data acquisition computer via a multiplexer (DSI Data Exchange Matrix).
  • the telemetry system enables the continuous recording of blood pressure, heart rate and body movements in awake animals in their usual habitat.
  • the studies are carried out on adult female rats with a body weight of> 200 g. After transmitter implantation, the test animals are kept individually in Makrolon® type III cages. You have free access to standard food and water. The day / night rhythm in the test laboratory is set by changing the room lighting.
  • the telemetry transmitters used e.g. PA-C40, HD-S10, DSI
  • PA-C40, HD-S10, DSI are surgically implanted in the test animals under aseptic conditions at least 14 days before the first test use.
  • the fasting animals are anesthetized with isoflurane (IsoFlo®, Abbott, introduction 5%, maintenance 2%) and the abdomen is shaved and disinfected over a large area.
  • the fluid-filled measuring catheter of the system is inserted cranially into the descending aorta above the bifurcation and attached with tissue adhesive (Vetbond TM, 3M).
  • the transmitter housing is fixed intraperitoneally to the abdominal wall muscles and the wound is closed in layers.
  • an antibiotic (Ursocyclin® 10%, 60 mg / kg sc, 0.06 ml / 100 g body weight, Serumwerk Bernburg AG, Germany) and an analgesic (Rimadyl®, 4 mg / kg sc, Pfizer, Germany) are administered postoperatively to prevent infections.
  • the test substances are dissolved in suitable solvent mixtures corresponding to an application volume of 2 ml / kg body weight.
  • a solvent-treated group of animals is used as a control.
  • the telemetry measuring device is configured for 24 animals.
  • the instrumented rats living in the facility are each assigned their own receiving antenna (RPC-1 Receiver, DSI).
  • the implanted transmitters can be activated externally via a built-in magnetic switch and are switched to transmission when the test is run.
  • the transmitted signals can be recorded online by a data acquisition system (Dataquest TM A.R.T. for Windows, DSI or Ponemah, DSI) and processed accordingly.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • MAP mean arterial pressure
  • HR heart rate
  • ACT heart rate
  • the acquisition of the measured values is computer-controlled and repeated every 5 minutes.
  • the source data collected as an absolute value are corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1, DSI).
  • the data are smoothed over a presettable time by determining the mean value (30 minute mean value).
  • the cardiovascular effect after administration of an sGC modulator, neprilysin inhibitor, angiotensin AII antagonist, and double and triple combinations thereof are shown by determining the long-term effects on hemodynamic and hormonal parameters in a high-renin, low-NO hypertension model in rats.
  • TGR transgenic Ren2 rats
  • the control group received a placebo, the test groups sGC modulators, neprilysin inhibitors, angiotensin AII antagonists, and double and triple combinations thereof for 4-10 weeks.
  • the rats in the placebo and treatment groups also received 30-100 mg / l L-NAME in the drinking water.
  • Systolic blood pressure and heart rate are measured weekly using the "tail-cuff" method in conscious animals in cages at a constant temperature of 37 ° C.
  • Urine collections take place on day 0, during and at the end of the experiment in metabolism cages and proteinuria, urinal electrolyte excretion is determined. At graduation, left ventricular pressure and cardiac contractility are measured under anesthesia. Finally, the animals are killed by decapitation and blood samples are taken. Plasma and urine parameters are determined biochemically e.g.
  • ANP (RIA Kit RK 005-24, Phoenix Pharmaceuticals, Inc., USA), cGMP (RIA Kit RE29075, IBL International GmbH, Germany), Renin, Angiotensin I (RIA Kit CA-1533, DiaSorin SpA, Italy) and aldosterone ( P2714, DiaSorin SpA, Italy).
  • Organs e.g. Kidney, heart, lungs, etc. are taken and gene expression profiles as well as histopathological data are collected.
  • sGC modulator sGC stimulator or sGC activator
  • neprilysin inhibitors angiotensin AII antagonists
  • double and triple combinations thereof are shown in a dog model of "mild" systolic heart failure caused by acute angiotensin AII antagonist-induced hypertension evaluated.
  • An animal experimental model of a left ventricular dysfunction is triggered by right ventricular "tachypacing" at 180 bpm for 10 days. The experimental implementation of this model has been described in detail. [ Redfield et al., Circulation 1993; 87: 2016-2022 ]
  • sGC modulator sGC stimulator or sGC activator
  • neprilysin inhibitors neprilysin inhibitors
  • angiotensin AII antagonists double and triple combinations thereof on blood pressure and heart rate
  • renal wrap double and triple combinations thereof on blood pressure and heart rate.
  • one kidney is wrapped in silk while the second kidney is occluded from the main renal artery becomes.
  • Page et al. Science 1939; 89: 2307-2308 ; Goldblatt et al., Proc Natl Acad Sci 1976; 73: 1722-1724 .
  • the dogs develop stable high blood pressure.
  • the compound of the formula (6) shows no hemodynamic effects (blood pressure, heart rate) at an oral dose of 0.1 mg / kg; With 0.3 mg / kg, a decrease in mean arterial blood pressure by approx. -10% and a transient increase in heart rate were observed.
  • the comparative substances administered orally as a double combination show a reduction in the mean arterial blood pressure of approx. -20% with associated reflex tachycardia in the dose tested.
  • the addition of 0.1 mg / kg of the compound of the formula (6) to the double combination leads, compared to the double combination alone, to a reduced reflex increase in the heart rate with the same lowering of the mean arterial blood pressure.
  • the combination of the compound of the formula (6) in a dosage of 0.3 mg / kg with a neprilysin inhibitor and an angiotensin AII antagonist shows an additional effect on lowering blood pressure.
  • a non-additive effect on the heart rate was observed in the attempt of the triple combination (no additive compensatory effect or reflex tachycardia).
  • 30 mg / kg sacubitril and 10 mg / kg valsartan are used.
  • the compound of the formula (29) shows a decrease in the mean arterial blood pressure by approximately -10% and 15%, respectively, and an associated reflex tachycardia.
  • the compound of the formula (29) shows reflex tachycardia at an oral dose of 1 mg / kg.
  • the comparison substances administered orally as a double combination show a reduction in the mean arterial blood pressure of approx. -15% in the dose tested.
  • the triple combination of the compound of the formula (29) with a neprilysin inhibitor and an angiotensin AII antagonist show an effect on lowering blood pressure. In the double and triple combination, 30 mg / kg sacubitril and 10 mg / kg valsartan are used.

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Claims (13)

  1. Combinaisons contenant un stimulateur de GCs choisi dans le groupe constitué par les composés des formules
    Figure imgb0089
    Figure imgb0090
    Figure imgb0091
    Figure imgb0092
    Figure imgb0093
     ou l'activateur GCs de formule
    Figure imgb0094
     le sacubitril et le valsartan ainsi que, à chaque fois, les sels, les solvates et les solvates des sels correspondants.
  2. Combinaisons selon la revendication 1 contenant un stimulateur de GCs choisi dans le groupe constitué par les composés des formules
    Figure imgb0095
    Figure imgb0096
    Figure imgb0097
    Figure imgb0098
    Figure imgb0099
     ou l'activateur de GCs de formule
    Figure imgb0100
     et l'hémipentahydrate de [3-((1S,3R)-1-biphényl-4-ylméthyl-3-éthoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-méthyl-2'-(pentanoyl{2"-(tétrazol-5-ylate)biphényl-4'-ylméthyl}amino)butyrate] trisodique ainsi que, à chaque fois, les sels, les solvates et les solvates des sels correspondants.
  3. Combinaisons selon la revendication 1 ou 2 contenant le stimulateur de GCs de formule
    Figure imgb0101
     ou l'activateur de GCs de formule
    Figure imgb0102
     et l'hémipentahydrate de [3-((1S,3R)-1-biphényl-4-ylméthyl-3-éthoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-méthyl-2'-(pentanoyl{2"-(tétrazol-5-ylate)biphényl-4'-ylméthyl}amino)butyrate] trisodique ainsi que, à chaque fois, les sels, les solvates et les solvates des sels correspondants.
  4. Combinaisons selon l'une quelconque des revendications 1 à 3, contenant le stimulateur de GCs de formule
    Figure imgb0103
     et l'hémipentahydrate de [3-((1S,3R)-1-biphényl-4-ylméthyl-3-éthoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-méthyl-2'-(pentanoyl{2"-(tétrazol-5-ylate)biphényl-4'-ylméthyl}amino)butyrate] trisodique ainsi que, à chaque fois, les sels, les solvates et les solvates des sels correspondants.
  5. Combinaisons selon l'une quelconque des revendications 1 à 3, contenant le stimulateur de GCs de formule
    Figure imgb0104
     et l'hémipentahydrate de [3-((1S,3R)-1-biphényl-4-ylméthyl-3-éthoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-méthyl-2'-(pentanoyl{2"-(tétrazol-5-ylate)biphényl-4'-ylméthyl}amino)butyrate] trisodique ainsi que, à chaque fois, les sels, les solvates et les solvates des sels correspondants.
  6. Combinaison selon l'une quelconque des revendications 1 à 5 pour une application dans un procédé pour le traitement et/ou la prophylaxie de maladies cardiovasculaires, de maladies rénales, de maladies des poumons, ainsi que pour le traitement et/ou la prophylaxie de maladies fibrotiques.
  7. Médicament contenant une combinaison selon l'une quelconque des revendications 1 à 5 en combinaison avec un excipient inerte, non toxique, pharmaceutiquement approprié.
  8. Médicament contenant une combinaison selon l'une quelconque des revendications 1 à 5 en combinaison avec un ou plusieurs principes actifs supplémentaires choisis dans le groupe constitué par des inhibiteurs de l'ECA, des inhibiteurs de rénine, des bêtabloquants, l'acide acétylsalicylique, un diurétique, des antagonistes du calcium, une statine, des dérivés de digitaline (digoxine), des sensibilisateurs du calcium, des nitrates ainsi que des antithrombotiques.
  9. Médicament contenant une combinaison selon l'une quelconque des revendications 1 à 5 pour une application dans un procédé pour le traitement et/ou la prophylaxie de maladies cardiovasculaires, de maladies rénales, de maladies des poumons, ainsi que pour le traitement et/ou la prophylaxie de maladies fibrotiques.
  10. Kit comprenant une composition pharmaceutique contenant le stimulateur de GCs de formule
    Figure imgb0105
     ou l'activateur de GCs de formule
    Figure imgb0106
     et une composition pharmaceutique contenant du valsartan et de l'acide N-(3-carboxy-1-oxopropyl)-(4S)-(p-phénylphényl-méthyl)-4-amino-2R-méthylbutyrique ou un ester correspondant.
  11. Kit selon la revendication 10 comprenant une composition pharmaceutique contenant le stimulateur de GCs de formule
    Figure imgb0107
     ou le composé de formule
    Figure imgb0108
     et une composition pharmaceutique contenant l'hémipentahydrate de [3-((1S,3R)-1-biphényl-4-ylméthyl-3-éthoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-méthyl-2'-(pentanoyl{2"-(tétrazol-5-ylate)biphényl-4'-ylméthyl}amino)butyrate] trisodique.
  12. Kit selon la revendication 11 comprenant une composition pharmaceutique contenant le composé de formule
    Figure imgb0109
     et une composition pharmaceutique contenant l'hémipentahydrate de [3-((1S,3R)-1-biphényl-4-ylméthyl-3-éthoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-méthyl-2'-(pentanoyl{2"-(tétrazol-5-ylate)biphényl-4'-ylméthyl}amino)butyrate] trisodique.
  13. Kit selon la revendication 11 comprenant une composition pharmaceutique contenant le composé de formule
    Figure imgb0110
     et une composition pharmaceutique contenant l'hémipentahydrate de [3-((1S,3R)-1-biphényl-4-ylméthyl-3-éthoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-méthyl-2'-(pentanoyl{2"-(tétrazol-5-ylate)biphényl-4'-ylméthyl}amino)butyrate] trisodique.
EP16739146.5A 2015-07-23 2016-07-15 Stimulateurs / activateurs de guanylate cyclase soluble en combinaison avec un inhibiteur de l'endopeptidase neutrale (nep) et un antagonist d'angiotensin ii et son utilisation Active EP3325013B2 (fr)

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WO2019022436A2 (fr) * 2017-07-27 2019-01-31 에리슨제약(주) Composition pharmaceutique comprenant un inhibiteur de nep et un bêta-bloquant
WO2019081456A1 (fr) * 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Utilisation d'activateurs et de stimulateurs de sgc comprenant une sous-unité bêta2
WO2019211081A1 (fr) * 2018-04-30 2019-11-07 Bayer Aktiengesellschaft Utilisation d'activateurs de la gcs et de stimulateurs de la gcs pour le traitement de déficiences cognitives
WO2021230664A1 (fr) * 2020-05-12 2021-11-18 에리슨제약(주) Composition pharmaceutique pour la prévention ou le traitement d'une insuffisance cardiaque et d'une cardiopathie ischémique, comprenant du sacubitril, du valsartan et du nébivolol, et formulation de complexe pharmaceutique comprenant celle-ci
KR20210138510A (ko) 2020-05-12 2021-11-19 에리슨제약(주) 사쿠비트릴, 발사르탄 및 네비보롤을 포함하는 심부전 및 허혈성 심질환의 예방 또는 치료용 약제학적 조성물 및 이를 포함하는 약제학적 복합제제
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